Reviewed: Engelman U, Walther C, Bondarenko B, et al. Efficacy and safety of a combination of Sabal and Urtica extract in lower urinary tract symptoms. Arzneim-Forschung/Drug Res. 2006;56(3):222-229.
More than 60% of males in the second half of life show evidence of benign prostatic hyperplasia (BPH), i.e., based on clinical observations of urinary symptoms and/or on histological examination. BPH may result in obstruction and irritation of the lower urinary tract with symptoms such as incomplete voiding, nighttime urination, and decreased urinary flow.
Two types of conventional pharmaceutical drugs have demonstrated efficacy in the treatment of these lower urinary tract symptoms (LUTS), although the etiology of BPH has not been fully elucidated. The 5-alpha-reductase inhibitors, such as finasteride (Proscar®, Merck), block the conversion of testosterone to dihydrotestosterone, which is believed to be responsible for some of the swelling of the prostate. The selective alpha1-adrenoceptor antagonists block post-synaptic alpha1-adrenergic receptors, resulting in relaxation of smooth muscle in the bladder neck and prostatic urethra. Drugs that act selectively on specific alpha-1 subtypes cause fewer unwanted side effects (e.g., sexual dysfunction) than 5-AR inhibitors.
In placebo-controlled studies, the selective alpha1A-adrenoreceptor antagonist tamsulosin (Flomax®, Boehringer-Ingelheim), has been shown to effectively reduce subjective LUTS symptoms within 2 weeks of initiating treatment. Improvement in peak urinary flow rate and residual urinary volume reached statistical significance after 4 weeks of treatment and reached maximum benefit after 12-14 weeks.
Plant extracts are also extensively used in many European countries in the management of BPH and they are becoming more popular in the United States. Saw palmetto (Serenoa repens [W. Bartram] Small, Arecaceae) fruit (berry) extract and stinging nettle (Urtica dioica L., Urticaceae) root extract are the most commonly used herbal preparations in Germany, where 61.6% of men with LUTS are treated with phytomedicines. In randomized, double-blind clinical trials, both of these extracts have demonstrated effectiveness in treating LUTS symptoms. A product that combines both extracts—PRO 160/120 (a fixed combination of 160 mg saw palmetto fruit extract, WS® 1473, and 120 mg stinging nettle root extract, WS® 1031 (both made by Dr. Willmar Schwabe GmbH & Co.)—has been shown in published clinical trials to improve peak urinary flow and improve subjective symptom scores on the International Prostate Symptom Score (IPSS) better than placebo and comparable to the drug finasteride.1 The IPSS is a self-rating questionnaire regarding lower urinary tract symptoms, including frequency, urgency, nocturia, weak stream, and incomplete emptying.
In the trial being reviewed here, researchers compared the efficacy and tolerability of PRO 160/120 to tamsulosin in patients with LUTS. The study was a prospective, randomized, double-blind, double-dummy, multicenter trial that utilized PRO 160/120. Tamsulosin in 0.4 mg slow-release capsules was purchased from the domestic market. (In a double-dummy design, both treatment groups receive an active treatment as well as a placebo, as explained below.)
The trial enrolled 149 subjects who were recruited from outpatients in 23 private urological practices and outpatient clinics in Germany. Study subjects were suffering from BPH not requiring surgery. Inclusion criteria included age ? 50 years, maximum urinary flow rate ? 12 ml/s at a urinary volume ? 150 ml, and initial IPSS total score ? 13. During a 2-week placebo run-in phase, 140 subjects were randomized to receive either 1 capsule 2 times per day of PRO 160/120 plus 1 capsule tamsulosin placebo per day (n = 71) or 1 capsule per day tamsulosin plus 1 capsule 2 times per day of the PRO 160/120 placebo (n = 69). After the baseline examination, follow-up visits were scheduled after weeks 8, 16, 24, 36, 48 and 60 of double-blind treatment. Safety of the treatments was monitored via physical examination, digital-rectal examination of the prostate, and laboratory tests at pre-treatment and after weeks 24 and 60.
Efficacy of treatment was assessed primarily by the change in the IPSS total score between baseline and at the end of the 60th week of treatment. Secondary outcome measures included peak urinary flow rate (measured by an electronic uroflow recorder), average urinary flow rate, urinary output, duration of micturition (urination) and flow increase, and residual urinary volume. The primary analysis, conducted on the intention to treat principle, was based on the full analysis set (FAS)—“all patients who were randomized and received the investigational treatment at least once….” After eliminating patients for protocol violations, the per protocol analysis (PP) was conducted on 78.9% (56 of 71) in the PRO 160/120 group and 78.3% (54 of 69) for the tamsulosin group. The subset of “responders”—patients who had an IPSS total score ? 7 at endpoint—was analyzed as well.
The FAS showed that the IPSS score decreased from a median of 20 points at baseline to a median of 11 points in the PRO 160/120 group and a median of 10 points in the tamsulosin group at week 60 (medians with 95% confidence interval). In both the FAS and PP analysis the median intraindividual decrease in the IPSS score was 9 points. The responder rate (IPSS ? 7 at endpoint) was 32.4% for PRO 160/120 (22 of 68 patients) and 27.9% for tamsulosin (19 of 68 patients) in the FAS (P = 0.034 for non-inferiority of PRO 160/120). The responder rates in the PP analysis were 32.1% (18 of 56) for PRO 160/120 and 29.6% (18 of 54) for tamsulosin (P = 0.074 for non-inferiority). Both treatments were also comparably effective in a sub-group analysis of patients with a baseline IPSS of ? 19 points (moderately severe symptoms) as well as in patients with a baseline score of ? 20 points (severe symptoms).
In the LUTS-based Quality of Life assessment (single item, range 0 [very good] to 6 [very bad]), the PRO 160/120 group improved by a median of 2 points, while the tamsulosin group improved by a median of 1 point (FAS, baseline versus treatment end). In the PRO 160/120 group, 36 patients (50.7% of 71), and in the tamsulosin group, 34 patients (49.3% of 69), showed an improvement in quality of life of at least 2 points. The authors write, “With a margin of 13% for non-inferiority of PRO 160/120, treatment with the herbal drug was significantly not inferior to treatment with tamsulosin (P = 0.04).”
Regarding the secondary outcome measures, both groups demonstrated “considerable improvement” in peak and mean urinary flow, and decreased the duration of urination and the amount of residual urine. Neither treatment had an effect on urinary volume, flow increase, prostate size, or sexual functioning.
The researchers concluded that the saw palmetto-nettle root combination phytomedicine was safer than the conventional drug. Fifteen PRO 160/120 patients (21.1% of 71) reported 18 adverse events (AEs) while 19 tamsulosin patients (27.5% of 69) reported 23 adverse events. Researchers assessed these AEs and classified 6 in the PRO 160/120 group and 9 in the tamsulosin group as being drug related. This corresponds to less than 1 AE in 1000 treatment days. The authors therefore rate both drugs as having excellent tolerability “albeit with a 30% advantage regarding AE rates in favor of PRO 160/120.”
In conclusion, the authors write that “this study supports the non-inferiority of the [herbal combination] extract PRO 160/120 in comparison to the well investigated and widely used alpha-1-adrenoceptor antagonist tamsulosin” for the amelioration of BPH-associated LUTS. The authors also concluded that “Both drugs reduced the subjective symptoms of BPH to a comparable, clinically relevant extent that had a direct, beneficial influence on the patients’ quality of life.” This trial should help restore some of the compromised public and professional perception of saw palmetto preparations for treating BPH symptoms that was adversely affected by the publication of a recent trial with a negative outcome, in which a saw palmetto extract did not provide statistically beneficial effects in patients with more advanced (moderate to severe) BPH symptoms.2
—Cathleen Rapp, ND
References
1. Sökeland J. Combined sabal and urtica extract compared with finasteride in men with benign prostatic hyperplasia: analysis of prostate volume and therapeutic outcome. Br J Urol. 2000(86):439–442.
2. Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign prostatic hyperplasia. New Engl J Med. 2006;354:557–566.